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Terahertz spectroscopy reveals that water helps proteins change shape

BioPhotonics
Oct 2008
Water is a “designer fluid” in living cells, researchers say

David L. Shenkenberg

Just about everyone takes water for granted. Now, using a technique called terahertz absorption spectroscopy, researchers at the University of Illinois at Urbana-Champaign have shown that water plays a more important role than previously thought.

Among other things, they found that water helps proteins fold into their natural structure, termed the native state. Proteins begin as a long chain of amino acids that folds into a more complex structure, and the way that proteins fold has a profound effect on their activity. However, biochemists often neglect water in their protein folding calculations.

One reason why water has been neglected is because it is transparent and therefore difficult to measure spectroscopically. “What has changed in the last few years is that spectroscopic methods that can actually look at the water have come online,” said chemistry professor Martin Gruebele, who oversaw the investigation.

BRDesigner_Ubinwater2.jpg

A simulation showing water molecules around an unfolded and a folded protein. The water molecules closest to the protein are highlighted bright red for effect. Terahertz spectroscopy has shown that the water molecules closest to the protein behave differently than the surrounding ones and actually participate in the folding process.

For about the past 20 years, nuclear magnetic resonance spectroscopy has been used to study water molecules, but it can monitor only the surface of the water. To go deeper, scientists had to use terahertz spectroscopy, but terahertz lasers have only recently become powerful enough to get a signal in spectroscopy experiments.

Terahertz means 1 trillion cycles per second, which corresponds to wavelengths from the microwaves to 1 mm long. Recently, terahertz lasers became commercially available.

Slaves to water

Gruebele and colleagues at the university and at Rurh-University Bochum in Germany used a terahertz spectrometer that they built in the lab to monitor the motion of water and proteins on a picosecond time scale. That’s one-trillionth of a second! They used a protein called ubiquitin, which gets its name because it is ubiquitous in cells, as described in the July 23, 2008, issue of Angewandte Chemie.

When they monitored the motion of the water molecules as ubiquitin folded into its native state, they found that the molecules moved into the natural configuration faster than the protein itself, which supports the work of Hans Fraunfelder at Los Alamos National Laboratory in New Mexico. Fraunfelder has said that the motion of proteins is “slaved” to the faster motion of water molecules.

In general, water around proteins absorbs more of the terahertz radiation than pure water. Gruebele compared the proteins with ice. “The proteins lock in the water like ice and prevent it from absorbing as much light,” he said, whereas the absorption increases once the ice melts and the water molecules are free to tumble around.

The ice analogy mirrors the real environment of the cell. Water in an organism is never more than a few nanometers away from proteins and other large molecules. Much of the water in cells is locked in and around proteins.

Like a fish

With all the proteins that the researchers have studied to date, the terahertz absorption of the water has decreased when they have used proteins with altered amino acids, and the absorption of water around completely unfolded proteins has looked like that of pure water. From these results, the researchers have concluded that the natural structure of the protein stores the most water. “We have no idea why that is,” Gruebele said.

But he speculates that water might enable some proteins, particularly enzymes, to draw biological molecules toward them. For example, enzymes could pull molecules into their active sites where they can modify the molecular substrates. “They might get sucked into a protein,” he said, “like a fish that sucks in water to get prey.”

Further research in this direction could have exciting applications. “One of the things that might come out of this [research] is that you can tailor the structure of the protein so that its function can be enhanced,” Gruebele said.

“Water can be viewed as a ‘designer fluid’ in living cells,” Gruebele said. But he knows that it may take a while for this idea to gain acceptance. “As you know, this sort of thing takes years and years before minds will eventually change,” he added.

The Anfinsen experiment has become a canonical way to explain protein folding. Christian B. Anfinsen showed that he could unfold a protein by breaking the sulfur-sulfur bonds from the amino acid cysteine and then refold the protein by restoring those disulfide bonds, an experiment for which he won one-half of the Nobel Prize in chemistry in 1972.

Although the Anfinsen experiment showed that the amino acid sequence and disulfide bonds are crucial to the folding process, his work was done in vitro. “If Anfinsen were around now, and he were seeing the water molecules, he might have agreed,” Gruebele said. “He did not intend for this to occur in a vacuum.” Proteins called chaperones also help other proteins fold in the cell, but that’s another story.


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